Hispanics, particularly those from the Caribbean Islands, currently represent 4 percent to 6 percent of population over age 65, but they are the most rapidly increasing ethnic group in this age category in the US. With the increase in numbers of Hispanic elderly, this ethnic group will face many of the diseases associated with advanced age, such as Alzheimer's disease (AD). We find evidence of a higher prevalence of AD among Hispanics in New York City, and the risk of developing AD in this population also appears to be increased. Mutations that result in an early onset, autosomal dominant form of AD have never been investigated in this growing population in the US. While we have found the epsilon4 polymorphism of APOE on chromosome 19 to only slightly increase risk of AD in Hispanics, we have also observed a 3-fold higher risk of AD among Caribbean Hispanics compared to Caucasians with the APOE-epsilon3/epsilon3 genotype. This implies the existence of other genes or environmental factors that increase AD risk. Appropriately designed, population-based investigations of environmental factors associated with AD are already in progress by our group. To identify genes that increase the risk of AD, families or sibling pairs are more appropriately studied. In this revised application, we hypothesize that one or more AD susceptibility genes, other than APOE, exist in Caribbean Hispanics. We will focus on the genetic influences on AD risk among patients and their siblings in the Caribbean Hispanic population in New York City and the Dominican Republic. Specifically, we propose to chromosomally localize genes that increase risk of AD by collecting detailed clinical information on 450 sib-pairs with AD in New York City and the Dominican Republic, continue to search for large, extended pedigrees with late-(or early-) onset AD, establish transformed cell lines in AD sib-pairs and families, conduct genetic linkage analyzes in the affected sib-pairs and extended pedigrees using semi-automated fluoresecently-labeled microsatellite genotyping and explore the genetic relationship of APOE to any mapped susceptibility locus. The ultimate goal of this project is to chromosomally localize genes that may increase the risk of AD among the Caribbean Hispanic ethnic group.